Sapogenin reduction product and preparation of same



Patented Oct. 27, 1942 UNITED STATES PATENT FFICE SAPOGENIN REDUCTIONPRODUCT AND PREPARATION OF SAME,

RussellEarl Marker, State College, 'Pa., assignor to Parke, Daviscorporation -of No Drawing.

Claims.

attached to ring D of the steroid skeleton.

Tschesche and Hagedorn (Ber. 68, 2247 (1935).) proposed theiormula forthe sapogenin, tigogenin, and later workers have, with reservations,acceptedthis formulation of thesteroidal sapogenin side chain. Othersapogenins suchias digitogenin, gitogenin, chlorogenin, diosgenin, andsarsasapogenin have been shown to differ from tigogenin only in regardto the connections between ring A and B, the degree of saturation of thering system, and the number of substituents attached to these rings.

These diiferences are shown below:

'ligogenin HO r H Gitogenin & Gompany, Detroit Mich a MichiganApplication February 17, 1941, Serial No. 379,359

CH3 CH3 AA I l I I H0 I HO OH OH Digitogenin "Chlorogenin CH3 CH2 I w ll HO HO \/H\/ Diosgenin Sarsasapogenin I have recently. suggested(Marker-8a Rohrmann, J. Am. Chem.Soc. 61, 846 (1939)) that a more likelystructurefor the side chainof these steroidal sapogenins is that shownbelow.

It is apparent that this formulation differs from that of Tschesche-andHagedorn in that the'linkage, C27-O, is transferred from 023 to C22.However, a profound difference in the natureof the functional characterof the side chain oxygen atoms is implied, for :while theTschesche-Hagedorn formulaisthat of an u,adi-tetrahydrofuryl derivative,the Marker-Rohrmann formula is that of a spiro-ketal.

Recently it has been found (Marker & Rohrmann, J. Am. Chem. Soc. 61,846, 1516, 2724, 3479 (1939); 62, 647, 896, 1162) that the side chain ofthe naturally occurring sapogenins exists in two modifications.Sarsasapogenin contains one type of side chain characterized by the factthat a sapogenin of this type is readily reduced according to theClemmensen procedure using alcoholic hydrochloric acid and amalgamatedzinc (Marker & Rohrmann, J. Am. Chem. Soc. 61, 846 (1939) to givetetrahydro derivatives in which the side chain has four more hydrogenatoms than in the sapogenins themselves. Tigogenin, gitogenin,digitogenin, and chlorogeni-n behave difierently from sarsasapogenin inthat they are not reduced by the Clemmensen procedure, that is to say,they are recovered unchanged after boiling with alcoholic hydrochloricacid and. amalgamated zinc. Isosarsasapogenin is converted under theconditions of the Clemmensen reduction to the sametetrahydrosarsasapogenin Tthat .sarsasapogenin itself yields. Thesefacts, and others which are cited in the references listed, appear to meto be best explained by assumin that the two types of steroidalsapogenin side chains differ in regard to optical isomerism about C22.Accordingly, when it is necessary to disting'uish between isomers aboutC22 I represent the two types of side chains by formulae of thefollowing type:

(Tigogenin type side chain) See especially Marker & Rohrmann, J. Am.Chem. Soc. 62, 896 (1940). Ordinarily where isomerism about C22 is notof importance, the formula for the sarsasapogenin type of side chainwill be used for configurations both of sarsasapogenin and ti-gogenintype.

These two types of sapogenin side chains appear to be subject to anequilibrium, the velocity of attainment of which is catalyzed by acidicreagents. The equilibrium is" influenced by the configuration of thehydrogen atom at C5, and it appears that the following rule holds true.For compounds of the allo series (cholestane type) the tigogenin type ofside chain is the more stable, while for compounds of the regular series(coprostane type) at C5 the sarsasapogenin side chain is the morestable.

For the purpose of greater clarification, the Marker-Rohrmannformulation of the side chain of the steroidal sapogenins will be usedin describing the invention. It is to be understood, however, that theprocesses and products of the present invention may be obtained by theuse of the methods herein to be described and these processes andproducts are claimed without any implications that the reactions andstructures involved will ultimately be proved to be as representedherein.

Now I have found that A -unsaturated sapogenins and their side chainhalogenated derivatives can be treated with mineral acid and zinc, underconditions more vigorous than those required merely to reduce a 3-ketogroup, to form new A -unsaturated sapogenin derivatives with alteredside chain. These substances may also be called A -unsaturatedtetrahydrosapogenins.

The A -unsaturated tetrahydrosapogenins are readily transformed in ringsA and B to yield other tetrahydrosapogenins, especially those of theallo series which have been hitherto inaccessible.

For example, the triacetate of tetrahydrodiosgenin may be oxidized withchromic anhydride in acetic acid at 45 C. to yield the new 'I-ketotetrahydrodiosgenin triacetate. This may be reduced with aluminumisopropylate and isopropyl alcohol to yield after hydrolysis and thenbenzoylation, the tetrabenzoate of 7-hydroxy-tetrahydrodiosgem'n. Onrefluxing this tetrabenzoate with dimethylaniline there is obtained thetribenzoate of '7-dehydro-tetrahydrodiosgenin. These transformations areshown below.

CH3 CH3 CH3 CH3 CH3 CH3 1 I CH-CHz-CHz-CHz-CH- CHzOAC7-Keto-tctrahydrodiosgcnin triacetate Al(OiPr); iPrOH; hydrolysis;benzoyl chloride +pyridine l T A vxica u 7-Hydroxy-tetrahydrodiosgenintctrabenzoate 7-Dehydro-tetrahydrodiosgcnin tribenzoate Alternatively,the triacetate of 7-ketotetrahydrodiosgenin may be reducedwithsodium-inalcohol to give 7 hydroxy-tetrahydrotigogenin:

OHa CH:

7-hydroxy-tetrahydrotigogenin Tetrahydrotigogenyl chloride;

On refluxing the latter with quinoline there is obtained' the compoundof the following iormula:

and this maybe warmed on the steambath with hydrogen peroxide in aceticacid to obtain 2- hydrox'yj-tetrahydrotigogenln.

,Again .tetrahydro ni tigogenenone can be.

new

treated with bromine in acetic acid to obtain the correspondingG-bromosubstitution product. 0n refluxing this with methanolic'hydrochloric acid thereis obtained tetrahydrochlorogenone representableby the following formula CH CH3 x /L/Jg double bond betweencsmand one ofC4 and C6,

and tetrahydrosapogenin' derivatives hydrolyzable totetrahydrosapogenins having a double bond between C5'and one of C4 andCo, said tetrahydrosapogenin compounds bearing in rings A and B togethernot more than three functional groups selected from the class consistingof double bonds, hydroxyl groups, groups hydrolyzable to hydroxylgroups,ketone groupsand groups hydrolyzable to ,ketone groups,

These new" sapogenin derivatives bear" an alteredside chain whichdifiers from the side chain of the sapogenins themselves by the presenceof fourmore hydrogen atoms. The new:tetrahydrosapogenins of my inventionshow certain characteristic reactions which distinguish them from thesapogenins them selves. Thus:

(a) Whereas-the sapogenins are: readily halogenated' in'the side chain,for example, by treatment with bromine in acetic acid, thetetrahydrosap'ogenins of the present invention show no tendency tohalogenate the side chain under comparable conditions; i I

(b) Whereas the sapogenins may be hydrogenated under'acidic conditions,in the side chain to give dihydrosapogenins, the tetrahydrosapogenins ofthe present invention show no tendency toadd hydrogen to the side chain;(0) Whereas the" sapogenins are readily oxidized: in the side chain byselenium dioxide with the formation .of a red precipitat of metallicselenium (for example when the sapogenins are heated for" a whileWith'selenium dioxide in a mixture of acetic acid and'benzene), thetetrahydrosapogenins" of the present invention are unafiecte'd in thesideuchain by treatment with selenium dioxide under'comparableconditions;

(11) Whereas injtheside chain of the sapogenins-bothof the oxygen atomsappear to beinert to the ordinary reagents used to determine thepresence: of hydroxyl, carboxylor ketone groups,thetetrahydrosap'ogenins of the present invention contain: in the sidechain two reactive oxygen atoms present as hydroxyl groupsa secondaryhydroxyl group anda primary hydroxyl group-- characterizedx byrtheinability to be esterified,. etherified and replaced by halogen ontreatment with reagents customarily used for this purpose.

The new tetrahydrosapogenin compounds of the present invention, namely,tetrahydrosapogenin compounds of th allo series at C5 (cholestane type)or containing a double bond between C5 and one of C4 and C6 are in manyregards similar to the tetrahydrosapogenin compounds having a coprostaneconfiguration at C5, as set forth .in my copending application, SerialNo. 351,148, filed August 3, 1940, in which the following structure wasshown:

for the side chain attached to ring D in these compounds. Thetetrahydrosapogenins having the coprostane configuration at C5 appear tocontain only one reactive oxygen atom and this oxygen atom appears to bepresent as a primary hydroxyl group. The new tetrahydrosapogenins of thepresent invention appear to contain the sametype of side chain as thatassigned to the tetrahydrosapogenins having the coprostane configurationat C5. However, the new tetrahydrosapogenins of the present inventioncontain two reactive oxygen atoms-one present as a secondary, the otheras a primary hydroxy1 group.

Another distinction between the known tetrahydrosapogenins and th newtetrahydrosapogenins of the present invention exists in how they may beprepared. The former ar all readily prepared by treatment ofv steroidalsapogenins having the coprostane configuration at C5, with alcoholichydrochloric acid and amalgamated zinc. The new tetrahydrosapogenincompounds of the present invention cannot all be prepared in thismanner. The new tetr'ahydrosapogenins having a double bond atC5 can beprepared by the action of mineral acid and zinc on A -unsaturatedsteroidal sapogenins, but tetrahydrosapogenins having the cholestaneconfiguration cannot be prepared in this manner. This latter group hasnow become available becaus they can be prepared by suitabletransformations in rings A and B from th A '-unsaturatedtetrahydrosapogenins. Methods for'transforming A -unsaturated steroidsinto other steroids having functional groups such as double bonds,ketone groups, hydroxyl groups and the like have been developed duringthe past decade and these methods can'now be applied to obtain a Widevariety of tetrahydrosapogenins having th allo configuration at C5. Somesuch transformations have already been illustrated and others are setforth in greater detail in the examples to follow.

To prepare the new A -unsaturated tetrahydrosapogenins I treat A-unsaturated steroidal sapogenins in an organic solvent with thecombination of a mineral acid and zinc. I find that for best results onemust make a careful choice of mineral acid and organic solvent used. Ifind especially that the use of a homogeneous solution is desirable, forif two phases are present during the reduction the yields areconsiderably diminished. For best results I prefer to use amalgamatedzinc and a solution containing from one to five parts of concentratedhydrochloric acid per ten parts of organic solvent, and as organicsolvent I prefer .to use a lower aliphatic alcohol such as methanol,ethyl alcohol or one of the two isomeric propanols."

My invention may be further'illustrated by the following examples:

Example 1 To g. of amalgamated zinc is added a solution of 5 g. ofdiosgenin in 500 cc. of ethanol. This is brought to a reflux and a totalof 150 cc. of concentrated hydrochloric acid is added over a period oftwo and one-half hours. Refluxing is continued for an additional thirtyminutes. Then the mixture is poured into water and extracted with ether.The ethereal solution is washed well with water, and then concentratedto a volume of about 20 cc., whereupon the product crystallizes. It isfiltered and recrystallized from ethyl acetate in which it is quiteinsoluble. This substance, tetrahydrodio'sgenin, has M. P. 178- 179 C.It maybe represented by the formula below:

H3 CH3 CH3 I Treatment of they above tetrahydrodiosgenin with boilingacetic anhydride'ifor fifteen minutes gives a triacetate, which, aftercrystallization from pentane has M. P. 119.5 C.

Tetrahydrodiosgenin triacetate (1.0 g.) is heated with a solution of 1g. of potassium hydroxide in 100 cc. of ethanol for fifteen minutes onthe steam bath. The solution is poured into water and extracted withether. The ethereal solution is washed free of ethanol and the ether isremoved. The crystalline residue is recrystallized from ethyl acetate,to give tetrahydrodiosgenin of M. P. 178-179 C.

Tetrahydrodiosgenin tribenzoate is prepared by adding benzoyl chlorideto a solution of tetrahydrodiosgenin in pyridine. After standingovernight, .the mixture is poured into water, the precipitate collectedand crystallized from ether and from acetone. Tetrahydrodiosgenintribenzoate as thus obtained has M. P. 166-167 C,

Example 2 A solution of 500 mg. of tetr-ahydrodiosgenin in 50 cc. ofacetic acid is shaken with 200 mg. of platinum oxide catalyst under 3atm. of hydrogen for two hours. The solution is filtered, the solventremoved in vacuo, and the residue crystallized from ether and from ethylacetate. As thus obtained tetrahydrotigogenin has M. P. -19'7 C. It isvery soluble in methanol and ethanol.

The triacetate of tetrahydrodiosgenin (100 mg.) is shaken in acetic acid(20 cc.) with 100 mg. of Adams catalyst under hydrogen at 3 atm. for onehour. The solution is filtered, poured into water and extracted withether. The ether is evaporated to give an oil which crystallizes whentreated with pentane and cooled in a carbon dioxide-ether bath. It isrecrystallized from pentane to give tetrahydrotigogenin triacetate of M.P. 67-68 C.

Tetrahydrotigogenin (100 mg.) is acetylated directly by refluxing forfifteen minutes with an excess of acetic anhydride. The productcrystallizes from pentane to give the triacetate of tetra- Thetriacetate of tetrahydrotigogenin i (500 tetrahydr o-M-tigogenenone, hasM. P. 163-4" C. mg.) is dissolved in a solution of 2' g. of potasandmaybe represented by the following forsium hydroxide in 100; cc. ofethanol and heated mula: on the steam bathfor thirty minutes. Themix- H30H3 I tureiis poured into water and extracted with H3 H3 ether.The-ethereal solution is concentrated and H GHNHZCHPOH CHEOHcrystallizedte give tetrahydrotigogenin, M. P. i I 195-197? 0. Thetribenzoate of tetrahydrotigogenin is pre- OH pared withbenzoyl chlorideand pyridine accord- I j I ing to the directions or Example 1. Theproduct 0: v crystallizes from ether and is thetribenzoate offitzraicllydrotigogenin. This tribenzoate has P. I Emmple 5 i I Example:3 (a) d-Diosgenyl chloride is prepared by treati ing diosgenin incarbon tetrachloride solution (a) To P of the inacfitate in the presenceof calcium carbonate with a sotetrahydrodiosgenin in. cc. of benzene isadded lution of phosphorous pentachloride .in carbon a 9 '9 1 selemous m75 1 disulfide. After i e-crystallization from acetone 97 petcem and themixture 20 the dediosgenyl chloride has M. P, 211-213 c, fluxeqwgorouslyp one 9 (b) d-Diosgenyl chloride is treated by the potassium acetate isadded and the mixture is l method of Example 1 with amalgamated zinc andmi g s fi 33 E t alcoholic hydrochloric acid, thereby obtaining gi ip.gf gi Y: gg gf gfi tetrahydro-ddiosgenyl chloride as white crystalsWashed free of acetic acid, the ether is removed i ii z ggg tga gysgggd-diosgenyl chloride i i fi i 'w t may be catalytically hydrogenated byshaking 5 fig ii g i it in acetic acid solution with one-tenth itsweight solution is Washed w Water, evaporated, and ttdit it ttfitfiiefiititfthiifiettiiitfi the residue crystallizedfrom acetone using norittered and the filtrate concentrated in vacuo The The product,.tetrahydro-i-hydroxydiosgenin, has

o residue may be crystallized from methanol'to 196 It may e representedha give white crystals of tetrahydro-d-tigogenyl lowing formula: Ych1oride CH CH3 CH3 The above examples illustrative of this inven- 3 dtion are subject to numerous variations which,

skilled in the art.

A5-unsaturated sapogenins which may be 40 treated with mineral acid andzinc to form A I unsaturated tetrahydro-sapogenins include: diosgeninand its esters such as the acetate, the o \(V benzoate and the like;diosgenyl halides such H as the chloride or the bromide; and3-desoxydiosgenin. Furthermore the side chain of the The mother 11 uorscan be eva orated to we a small amount of the substance represent bleAs'unsaturated Steroldal Sapogemns employed may be of either thesarsasapogenin or of the by the formula" tigogenin type. Also instead ofusing the A CH3 CH3 CH3 CH3 unsaturated sapogenins the correspondingside re-cmomom-Jzn-on chain halogenated derivatives of A -unsaturatedsapogenins having either the sarsasapogenin or I the tigogenin type ofside chain may be employed in the practice of this invention withresults \/\OH as satisfactory as those obtained with the parentunhalogenated sapogenins. Certain transforma- HO/\/\ tions ofsubstituents which may be attached to g Ca may occur simultaneously withthe reduction H of the sapogenin side chain. For example, ester (1)) Amixture of 1 g. of tetrahydro-l-hydroxygroups, Such as an acetoxy groupat C3, may be diosgenin, 0.1 g. of platinum oxide catalyst and c0saponified to hy roxyl groups. Nuclear halo en 100 cc. of acetic acid isshaken under hydrogen groups such as a chlorine atom at C3 r us lly atthree atmospherespressure for an hour. Then unaffected dilrmg hrefluctlonthe mixture is filtered and the filtrate concen- Other modesIsolating a d purifyin the trated in vacuo. The residue may becrystallized tetrahydmsapogenms Of i ventlon may be from methanol togive tetrahydro--hydroxyused instead of extraction with ether andcrystaltigogenin as white crystals lization as indicated in theexamples. The method selected for isolation and purification of Example4 a particular tetrahydrosapogenin will be deter- (a)Tetrahydro-4-hydroxydiosgenin (1.0 g.) is mined by its properties, butin general the methdissolved in 100 cc. of ethanol containing 5 cc. odswill employ customary procedures in this art, of concentratedhydrochloric acid. The solution Su h as partition between immiscibleSolvents, is refluxed for ten minutes, then poured into high v udistillation, o at aph c adwater and extracted with ether. The etherealsorption and like devices. solution is washed, evaporated, and theresidue While I have described and illustrated certain crystallized fromethyl acetate. The product, 7 forms of my invention and have set theseforth 7/ in view of this disclosure will be apparent to'those in termsof a particular theory, I Wish it to be understood that my invention isnot to be limited to these forms, nor is its operability in any wiseafiected by the ultimate correctness of the particular theory hereinemployed,

What I claim as my invention is:

1. Process for the preparation of a steroidal sapogenin derivative whichcomprises treating a member of the class consisting of A -unsaturatedsteroidal sapogenins and side chain halogenated A -unsaturated steroidalsapogenins, while in an organic solvent with a mineral acid and zinc,under conditions more vigorous than those required merely to reduce anuclear B-keto group, thereby forming a tetrahydrosapogenin compound.

2. Process according to claim 1 in which the mineral acid is a member ofthe class consisting of hydrochloric acid and hydrobromic acid.

3. Process according to claim 1 wherein the organic solvent is a loweraliphatic alcohol.

4. Process according to claim 1 wherein the zinc has previously beenamalgamated.

5. Process for the preparation of a steroidal sapogenin derivative whichcomprises treating a member of the class consisting of M-unsaturatedsteroidal sapogenins and side chain halogenated steroidal sapogenins,while in a lower aliphatic alcohol solvent with hydrochloric acid andamalgamated zinc, under conditions more vigorous than those requiredmerely to reduce a nuclear 3-keto group, thereby forming atetrahydrosapogenin compound.

6. Process for the preparation of tetrahydrodiosgenin which comprisestreating diosgenin while in an organic solvent with a mineral acid andzinc, under conditions more vigorous than those required merely toreduce a nuclear 3-keto p.

'7. Process according to claim 6 in which the mineral acid is a memberof the class consisting of hydrochloric acid and hydrobromic acid.

8. Process according to claim 6 wherein'the organic solvent is a loweraliphatic alcohol..

9. Process accordingto claim 6- wherein the zinc has previously beenamalgamated.

10. Process for the preparation of tetrahydrodiosgenin which comprisestreating diosgenin, while in a lower aliphatic alcohol solvent withhydrochloric acid and amalgamated zinc, under conditions more vigorousthan those required merely to reduce anuclear 3-keto group.

11. A tetrahydrosapogenin compound selected from the class consisting oftetrahydrosapogenins having the cholestane configuration at C5,tetrahydrosapogenin derivatives hydrolyzable to tetrahydrosapogeninshaving the cholestane configuration at C5, tetrahydrosapogenins having adouble bond between C5 and one of C4 and Cs, and tetrahydrosapogeninderivatives hydrolyzable to tetrahydrosapogenins having a double bondbetween C5 and one of C4 and Cs; said tetrahydrosapogenin compoundsbearing in rings A and 3 together not more than three functional groupsselected from the class consisting of hydroxyl groups, groupshydrolyzable to hydroxyl groups, ketone groups and groups hydrolyzableto ketone groups.

12. A tetrahydrosapogenin compound having the cholestane configurationat C5 and substituted in rings A and B together by not more than threehydroxyl groups.

13. Tetrahydrodiosgenin.

14. Tetrahydro-M-tigogenenone.

15. Tetrahydrotigogenin.

RUSSELL EARL MARKER.

